Emerging roles of ARHGAP33 in intracellular trafficking of TrkB and pathophysiology of neuropsychiatric disorders

Takanobu Nakazawa (), Ryota Hashimoto (), Kazuto Sakoori, Yuki Sugaya, Asami Tanimura, Yuki Hashimotodani, Kazutaka Ohi, Hidenaga Yamamori, Yuka Yasuda, Satomi Umeda-Yano, Yuji Kiyama, Kohtarou Konno, Takeshi Inoue, Kazumasa Yokoyama, Takafumi Inoue, Shusuke Numata, Tohru Ohnuma, Nakao Iwata, Norio Ozaki, Hitoshi Hashimoto, Masahiko Watanabe, Toshiya Manabe, Tadashi Yamamoto, Masatoshi Takeda and Masanobu Kano ()
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Takanobu Nakazawa: Graduate School of Medicine, The University of Tokyo
Ryota Hashimoto: Osaka University Graduate School of Medicine
Kazuto Sakoori: Graduate School of Medicine, The University of Tokyo
Yuki Sugaya: Graduate School of Medicine, The University of Tokyo
Asami Tanimura: Graduate School of Medicine, The University of Tokyo
Yuki Hashimotodani: Graduate School of Medicine, The University of Tokyo
Kazutaka Ohi: Osaka University Graduate School of Medicine
Hidenaga Yamamori: Osaka University Graduate School of Medicine
Yuka Yasuda: Osaka University Graduate School of Medicine
Satomi Umeda-Yano: Osaka University Graduate School of Medicine
Yuji Kiyama: Institute of Medical Science, The University of Tokyo
Kohtarou Konno: Hokkaido University Graduate School of Medicine
Takeshi Inoue: Institute of Medical Science, The University of Tokyo
Kazumasa Yokoyama: Institute of Medical Science, The University of Tokyo
Takafumi Inoue: School of Advanced Science and Engineering, Waseda University
Shusuke Numata: Course of Integrated Brain Sciences, School of Medicine, University of Tokushima
Tohru Ohnuma: Juntendo University School of Medicine
Nakao Iwata: Fujita Health University School of Medicine
Norio Ozaki: Nagoya University Graduate School of Medicine
Hitoshi Hashimoto: iPS Cell-based Research Project on Brain Neuropharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University
Masahiko Watanabe: Hokkaido University Graduate School of Medicine
Toshiya Manabe: Institute of Medical Science, The University of Tokyo
Tadashi Yamamoto: Institute of Medical Science, The University of Tokyo
Masatoshi Takeda: Osaka University Graduate School of Medicine
Masanobu Kano: Graduate School of Medicine, The University of Tokyo

Nature Communications, 2016, vol. 7, issue 1, 1-17

Abstract: Abstract Intracellular trafficking of receptor proteins is essential for neurons to detect various extracellular factors during the formation and refinement of neural circuits. However, the precise mechanisms underlying the trafficking of neurotrophin receptors to synapses remain elusive. Here, we demonstrate that a brain-enriched sorting nexin, ARHGAP33, is a new type of regulator for the intracellular trafficking of TrkB, a high-affinity receptor for brain-derived neurotrophic factor. ARHGAP33 knockout (KO) mice exhibit reduced expression of synaptic TrkB, impaired spine development and neuropsychiatric disorder-related behavioural abnormalities. These deficits are rescued by specific pharmacological enhancement of TrkB signalling in ARHGAP33 KO mice. Mechanistically, ARHGAP33 interacts with SORT1 to cooperatively regulate TrkB trafficking. Human ARHGAP33 is associated with brain phenotypes and reduced SORT1 expression is found in patients with schizophrenia. We propose that ARHGAP33/SORT1-mediated TrkB trafficking is essential for synapse development and that the dysfunction of this mechanism may be a new molecular pathology of neuropsychiatric disorders.

Date: 2016
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DOI: 10.1038/ncomms10594

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